Since 1998, the Acute Liver Failure Study Group (ALFSG) has provided a network of sites across the United States, dedicated to learning and disseminating new knowledge about acute liver failure, a super-orphan condition that frequently kills young people and involves high resource utilization, despite its rarity. Few, if any, treatments have become available to preserve liver function and avoid the dire consequences of the sudden loss of hepatocyte mass. ALFSG has collected and disseminated important clinical information and bio-samples on more than 2,500 patients and conducted a controlled trial of N-acetylcysteine and a safety trial of ornithine phenylacetate (OPA) as putative treatment options. In addition, ALFSG has provided new insights into the central role of acetaminophen (APAP) in ALF in United States patients and further characterized many of the other etiologies such as hepatitis A, hepatitis B, autoimmune hepatitis and ischemic liver disease as well as focusing on disease outcomes and the role of transplantation. More than 90 ancillary studies have been initiated utilizing our data and bio- samples, generating ~70 original articles on all aspects of ALF. With our realignment of sites in 2010 and subsequent addition of 4 more sites, enrollment has increased, and this will facilitate more rapid completion of forthcoming trials. The correct assessment of etiology and prognosis on admission are vital to the management of ALF. Our new initiatives are directed at strengthening our diagnostic and prognostic assessments with further testing via point-of-care assays: the acetaminophen adduct assay, a dynamic measure of hepatic mass (methacetin breath test), evaluation of the role of coagulation factors in the condition (utilizing the ROTEM thromboelastogram), and finally testing the efficacy of OPA as an ammonia-trapping agent to ameliorate encephalopathy and brain edema. Additional approaches will include careful analyses of causality, fine tuning of prognostic assessments and, possibly, and the possible introduction of a liver support machine in the latter part of the grant cycle. Continuing studies of genomics, cytokines, coagulation and hepatic regeneration, compliment the clinical work and continue to make ALFSG a landmark research network and resource for other investigators.